Review Article Underestimating the Toxicological Challenges ...assessment of herbal medicine [ , ]. Apart from the toxicity of the intended herb(s) itself, the lack of a stringent

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013, Article ID 804086, 9 pageshttp://dx.doi.org/10.1155/2013/804086

Review ArticleUnderestimating the Toxicological Challenges Associated withthe Use of Herbal Medicinal Products in Developing Countries

Vidushi S. Neergheen-Bhujun

Department of Health Sciences, Faculty of Science and ANDI Centre of Excellence for Biomedical and Biomaterials Research,University of Mauritius, Reduit, Mauritius

Correspondence should be addressed to Vidushi S. Neergheen-Bhujun; [email protected]

Received 30 April 2013; Accepted 20 August 2013

Academic Editor: Brad Upham

Copyright © 2013 Vidushi S. Neergheen-Bhujun. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Various reports suggest a high contemporaneous prevalence of herb-drug use in both developed and developing countries. TheWorld Health Organisation indicates that 80% of the Asian and African populations rely on traditional medicine as the primarymethod for their health care needs. Since time immemorial and despite the beneficial and traditional roles of herbs in differentcommunities, the toxicity and herb-drug interactions that emanate from this practice have led to severe adverse effects and fatalities.As a result of the perception that herbal medicinal products have low risk, consumers usually disregard any association betweentheir use and any adverse reactions hence leading to underreporting of adverse reactions.This is particularly common in developingcountries and has led to a paucity of scientific data regarding the toxicity and interactions of locally used traditional herbalmedicine.Other factors like general lack of compositional and toxicological information of herbs and poor quality of adverse reaction casereports present hurdles which are highly underestimated by the population in the developing world. This review paper addressesthese toxicological challenges and calls for natural health product regulations as well as for protocols and guidance documents onsafety and toxicity testing of herbal medicinal products.

1. Introduction

With the burst in the use of herbal medicinal products(HMPs) globally, either for primary treatment or as com-plementary and alternative medicine, safety and efficacy ofherbal medicine have become a public health concern. Tilldate, it has been difficult to make reliable estimates of illhealth caused by herbal products particularly because (i)the perception that “natural” equates to “safe” and thereforeherbal medicine users would not realise that a herbal remedymay be responsible for adverse symptoms they have experi-enced; (ii) the lack of communication between patients andmedical practitioners regarding the use of herbal medicine;(iii) the presence of low-grade herbal products on themarket,and (iv) the supply of counterfeit products.

The World Health Organisation (WHO) estimates that80% of Asian and African populations rely on traditionalmedicine as the primary method for health care needs. Thescenario in developed countries is very similar with 70%

to 80% of the population using some form of complemen-tary and alternative medicine [1]. Commonly used singleherbs and polyherbal formulations in developing nations aredescribed in Tables 1 and 2. Whilst conventional medical sci-ence has powerful methodologies for proving efficacy, ensur-ing quality, standardising good manufacturing practices,testing for safety, and conducting postmarketing surveillancefor adverse effects, similar guidelines are lacking for herbalproducts; the same has not been extended to traditionalherbal medicines despite these having been embraced bydifferent cultures and regions. It must, however, be acknowl-edged that a number of protocols documents on safety andtoxicity testing of HMPs have been put forward by the Unionof Pure and Applied Chemistry [2], the European MedicinesAgency (EMEA) [3], and the European Food SafetyAuthority[4] though they are not followed by all countries. In addition,with the rising demand of medicinal plants from developedcountries, international trade particularly via the Internet hassoared. However international trade in medicinal plants is

2 BioMed Research International

Table 1: List of selected medicinal plants used as single herbs in developing countries.

Country Family Scientific name of plant Vernacular name Parts used Local medicinal uses Reportedliterature

MauritiusIsland

Rutaceae Aegle marmelos Bael FruitLeaf

Gastrointestinal disorderDiabetes [7–10]

Erythroxylaceae Erythroxylum laurifolium Bois de ronde Diuretic, used againstrenal stores [11, 12]

Ebenaceae

Diospyros neraudii,Diospyros revaughanii,Diospyros tesselleria,Diospyros melanida

Ebene Stem bark

Antibacterial,antifungal,antiviral, anthelminthic,antiprotozoal, andantimalarial

[11–13]

ReunionIsland

Aphloiaceae Aphloia theiformisChange ecorce,Goyave marron Leaf Treat fever and

antimalarial properties[14]

Asteraceae Eupatorium triplinerve Ayapana Aerial parts

MadagascarIsland

Acanthaceae Justicia gendarussa Ayapana marron Aerial partsAntimalarial properties [15]Buddlejaceae Nuxia sp. Vlier Leaf, bark

Asteraceae Psiadia sp. Arina/Iary Aerial parts

South Africa Podocarpaceae Podorcarpus sp. Fern pine LeafStem

Fevers, asthma, cough,cholera, arthritis,rheumatism, painfuljoints

[16]

Apocynaceae Carissa edulis Conkerberry Root Diarrhoea [17]

East Africa

Rutaceae Toddalia asiaticaNyalwet-kwach/Kaule/Mdakakomba

Root, bark,leaf, fruit

Malaria, cough, chestpain, sore throat [18]

Annonaceae Uvaria scheffleri Mguma RootLeaf Antimalarial activities [19]

North AfricaApiaceae Carum carvi El-qarwiya

(Caraway) Seed Diabetes andhypertension [20]

Compositae Artemisia herba-alba Chih(White mugwort) Leaf, root

WestAfrica Annonaceae

Annickia chlorantha Yellow Moambe Stem Bark

Aches, wounds, boils,vomiting, fever, chills,sore, spleen in children,and hepatitis

[21]

Anonidium mannii Eborne Afan StemBark

Measles, diarrhea,enlarged spleen, fever,gonorrhoea, productionof breast-milk

NortheastIndia

Acanthaceae Justicia adhatoda Nongmangkhaangouba

LeafFruit Asthma

[22]Acoraceae Acorus calamus Ok hidak RootLeaf Haemorrhoids

Meliaceae Aphanamixis polystachya Heirangkhoi Leaf Asthma

South IndiaEuphorbiaceae Acalypha indica Kuppaimeni Leaf Bronchitis

[23]Amaranthaceae Aerva lanata Sirukanpeelai Root DiabetesAcanthaceae Asystasia gangetica Medday keerai Whole plant Rheumatism

China

Rosaceae Agrimonia pilosa Xian he cao Whole plant Anti-inflammatory,against worms

[24]Asteraceae Erigeron breviscapus Dengzhanxixin Whole plantInflammation,high blood pressure, andheadache

Geraniaceae Geranium strictipes Geshanxiao Root Gastrointestinaldisorders

BioMed Research International 3

Table 2: Selected polyherbal formulation used in traditional medicine in developing nations.

Country Polyherbalformulation Herbal composition Vernacular name Parts used Medicinal purpose Reported

literature

IndiaPolyherbalhepatoprotectiveformulation (PHF)

Emblica officinalisTerminalia chebulaTerminalia belliricaPicrorhiza kurroaTinospora cordifoliaSwertia chirata,Azadirachta indica,Adhatoda vasica

AamlaHaritakiVibhitakaKutkiGuduchiFelwortsNeemAdusa

FruitsFruitsFruitsStemRhizomesEntire herbBarkStem bark

Hepatic disease [25]

China Wu-Zi-Yan-Zong

Cuscuta chinensisLycium barbarumRubus chingiiSchisandra chinensisPlantago asiaticaEpimedium brevicornum

StrangleweedChinese wolfberryRaspberriesPinyinChinese plantainYin Yang huo

FruitFruitFruitFruitFruitHerb

Neuroinflammatorydisease [26]

PakistanPHOE(Polyherbal oilextract)

Linum usitatissimumTrachyspermum ammiMyristica fragransSyzygium aromaticumColchicum luteumCelastrus paniculataPinus roxburghii

Alsi, Tuke KatanAjwain DesiJawatriLongSuranjan TalkhMal KangniBehroza

SeedsSeedsSeedsFlower budsRoots or tuberSeedsOleo-resin

Antinociceptive andanti-inflammatory [27]

not well regulated, with limited data available on the productidentity, on the true demand and supply, and on the priceof the unprocessed raw materials and the processed HMPs[5]. Although there exists the WHO certification schemeto regulate the quality of HMPs in international commerce,noncompliance with this certification further accentuates theproblems of adverse reactions [6].

Adverse health effects associated with herbal productsexist since time immemorial though and could be attributedto both the inherent toxic effects of herbal medicine andtoxicities induced by adulterants/contaminants.The low inci-dence of adverse reports associated with HMPs in developingcountries may be explained by the fact that consumersgenerally regard them as safe and therefore believe theirsymptoms are not attributable to the use of those products.In addition, the reluctance to indicate the concomitant useof HMPs to health care professionals, the impression thatthe adverse effects are known, forgetfulness, unwillingness toreport based on suspicion alone, pressures of clinical practice,and uncertainty about the reporting process are key factorswhich if addressed can certainly help in risk mitigation.Whilst evidence-based studies indicating the efficacy ofherbal drugs are still being unveiled, increasing evidence,regarding side effects of herbal medicine, has highlighted thedemand for and consequently the necessity of toxicologicalstudies for herbal products.

With the increased discussion on safety assessmentof herbs, toxicology constitutes an essential role in thedevelopment of herbal medicines and advancements ofanalytical techniques and molecular technology, in partic-ular the “-omic-” technology comprising transcriptomics,proteomics, and metabonomics, can make a significant

contribution to the predictive and preclinical toxicologyassessment of herbal medicine [28, 29].

Apart from the toxicity of the intended herb(s) itself,the lack of a stringent and harmonised quality control andeffective monitoring system imposed on herbal medicationsmay lead to contamination or adulteration that could proveharmful to humans. Possible contaminants/adulterants suchas heavy metals, pesticides, toxic herbs, and conventionaldrugs are commonly encountered toxicological concernsin herbal preparations. Nevertheless, strategies in devisingsuitable toxicological examination protocols to deal with thewide panoply of components in herbal drugs stand as achallenge to toxicologists.

Heavy metal contaminants like cadmium (Cd), arsenic(As), and lead (Pb) can be a risk factor in contributing to thetoxicity of these herbal products [30]. The WHO maximumpermissible limits of As, Cd, and Pb are 1.0, 0.3, and 10 ppm,respectively [31], with agricultural practices and industrialemissions being accounted as indirect contributors [32, 33].Hence, a recent study by Affum et al. [34] showed the levelof arsenic in ready-to-use aqueous-based antimalaria herbalmedicine in Ghana to be above the WHO permissible levels.Plant material may also be contaminated with pesticides andsubsequent poor manufacturing practices may lead to con-tamination with bacteria, fungi, and other microorganisms.In addition, an increasing number of herbal supplementshave been found to be adulterated with active pharmaceuticalproducts [35].

Case reports have played a crucial role in alerting thescientific community on the adverse effects of therapeuticinterventions [36, 37]. This is particularly true for herbalmedicines, many of which have a long traditional use but


without ever having been submitted to formal tests of safetycompared to conventionalmedicines.Moreover, despite theirimportance, case reports are often of poor quality, a factthat can seriously limit their value [38]. Hence, many of thecase reports in the developing countries are not properlyrecorded, limiting appropriate conclusion thereby contribut-ing to increasing adverse clinical effects of herbal remedies.

2. Evidence-Based Herbal Drug Toxicity

Toxicological problems associated with the use of herbalmedicines are complex but have been regularly associatedwith serious adverse fatalities ranging from cardiovascularproblems to psychiatric to neurological effects to liver toxicityor malfunction to hematologic and renal toxicity [39–41].The diagnoses of herbal toxicity are usually made afterconsideration of the temporal relationship between exposureto the herb and the occurrence of the adverse event and byexcluding other causes. However, causality assessment usingappropriate tools for ascertaining herbal toxicity in a numberof cases has failed to show any causal effects or has indicatedonlyweak causal relationship [42, 43]. For instance, the reportof toxic liver injury due to consumption of the herb GreaterCelandine (Chelidonium majus L.) in patients from variousEuropean countries has been a matter of concern. Teschkeet al. [43] provided evidence of the existence of GreaterCelandine hepatotoxicity as a distinct form of herb-inducedliver injury in 22 spontaneous cases in Germany, but due topoor data quality the causal association between the herbusage and liver injury was less strong than hitherto assumed.

Moreover, althoughweak or no causality of herbal toxicitycould be shown in many instances, a number of studiesstill have reported the potentially toxic nature of herbaldrugs. In 1992, in Belgium, consumers of a herbal weight-loss preparation containingAristolochia spp. exhibited severerenal disease manifested by interstitial fibrosis, which rapidlyprogressed to renal failure [44]. Moreover, Aristolochia spp.also used as an aphrodisiac, as an anticonvulsant, as animmune stimulant, and to treat arthritis, gout, rheumatism,eczema, wound treatment, allergic gastrointestinal colic, andgallbladder colic have been subsequently reported to impairrenal function due to the presence of aristolochic acid [45,46]. In 1995, in Southern Taiwan and Japan, the use ofSauropus androgynus in weight control was associated withan outbreak of Sauropus androgynus-related obstructive lungdisease [47]. Jones and Lawson [48] reported that the useof blue cohosh herbal medication was associated with pro-found neonatal congestive heart failure. The effect could beattributed to the presence of vasoactive glycosides and to analkaloid known to produce toxic effects on the myocardium.Furthermore, blue cohosh has sympathomimetic and directcardiotoxic effects, which can cause coronary vasoconstric-tion and decrease oxygen flow to the heart, thereby leadingto morbidity and mortality in the foetus or in newborninfant exposed via maternal ingestion [48]. Similarly, cardiacglycosides have been linked with hyperkalaemia, a side effectobserved in a patient taking a long list of herbal medicinaldrugs [49].

Similarly, in 2005, clinical problems arising from theuse of herbal medicines were reported in Hong Kong andAristolochia species was found responsible for acute renalfailure (𝑛 = 1), with aconite roots causing aconitinepoisoning (𝑛 = 2), theDatura species causing anticholinergicpoisoning (𝑛 = 1), and “yulan” (Stephania sinica) causingtetrahydropalmatine poisoning (𝑛 = 3) [50]. Likewise, in2007, a systematic survey in Swiss hospitals indicated 10 casesimplicating Herbalife, a herbal product sold for promoting“wellness” and weight reduction, as a possible cause ofpotentially severe hepatotoxicity. However it should be notedthat the causality assessment in these cases was conducted bythe WHO global introspection method, which is not liver-specific and therefore not a reliable tool to ascertain causalityin presumed hepatotoxicity cases. Causality assessment ofhepatotoxicity cases requires the Council for InternationalOrganisations of Medical Sciences (CIOMS) methods. Thus,for the 10 cases, a number of parameters for a valid causalityassessment were not reported and there was also a case ofhepatitis E explaining the presence of liver disease [51].

The diagnosis of herbal-drug-induced hepatotoxicitycontinues to be a challenge despite the availability of causalityassessment tests. There are only limited number of clinicalstudies with HMPs reported in the literature despite thefact that they have been used for centuries. Thus post-market pharmacovigilance providing interesting source ofsafety information and causality assessment indicates a linkbetween an observed adverse event to a suspected HMP[52]. Although there is no universally accepted method forcausality assessment, the existing methods rely on algorith-mic, probability-based, and expert analyses as well as onthe quality of adverse reactions reports. Unless causality isestablished, narrative reports remain less convincing of anyherbal adverse reactions.

Cases with severe intoxications in humans have also beenreported after consumption of essential oil rich in thujone.Thujone or thujone-containing products have been reportedto cause central nervous system disturbances which canlead to convulsions and ultimately to unconsciousness anddeath [53]. Similarly, licorice (Glycyrrhiza glabra) commonlyused for inflammation of the upper respiratory tract andgastric and duodenal ulcers has been reported to causesuppression of the renin-aldosterone system, resulting insodium and water retention, hypokalemia, hypertension,cardiac arrhythmias, and myopathy in cases of prolongeduse [54, 55]. Also, 10 deaths and 13 permanent disabilitiesfrom Ephedra-containing herbal drugs were reported to theFDA and the effects with ascribed to its sympathomimeticeffects [41, 56]. Overall, it is seen that while, on one hand, thetoxic effects of herbs have been widely reported in developedcountries, the same has not received an equivalent depth ofscrutiny in developing countries.

The toxicity of herbs may also result from the generationof reactive intermediates through metabolic activation ofherbal constituents via phases I and II reactions withinthe human body. The resultant reactive intermediates canbind covalently to DNA and proteins, leading to organtoxicity, mutagenicity, and even carcinogenicity. For instance,aristolochic acids in Aristolochia spp. used in a number of


Chinese traditional medicine undergo reduction of the nitrogroup by hepatic CYP1A1/2 or peroxidases in extrahepatictissues generating highly reactive cyclic nitrenium ions. Thelatter can react with DNA to form promutagenic DNAadducts such as 7-(deoxyadenosin-N6-yl) aristolactam I and7-(deoxyguanosin-N2-yl) aristolactam I as well as protein,resulting in activation of H-ras and myc oncogenes andgene mutation in renal cells and finally carcinogenesis of thekidneys [57, 58]. In vitro studies have also indicated the roleof herbal reactive intermediates in irreversibly inhibiting var-ious cytochrome enzymes (CYPs). However, the discrepancyof effects between in vitro, animal, and human studies reflectsthe significance of herbal dosing in the modulation of CYPs[58].

Other factors compromising safety may result from herbsharvested from polluted sites or poor farming practices,medicinal plant products contaminated with pesticides andmicrobial contaminants, heavy metals, toxic substances, andadulterants which can be toxic to the consumer.

3. Evidence-Based Drug Herbal Interactions

The contemporary use of herbal medicine is widespreadbut the challenge that society faces with its use is whethera patient will divulge to his or her medical practitionerthe concurrent use of herbal products with conventionalpharmacotherapy. A number of observational studies haveshown the negative or conflicting interactions of drugs andherb though theoretically herb-drug interactions could alsobe positive or neutral [59]. Herbal drugs usually contain amultitude of pharmacologically active ingredients, a fact thatgreatly increases the possibilities of interactions. In manyinstances, the likelihood of herb-drug interactions could behigher than drug-drug interactions. Interactions betweenherbs and drugs may increase or decrease the pharmaco-logical or toxicological effects via the pharmacokinetic herb-drug interactions caused by onemedicine interferingwith theelimination, metabolism, or absorption of another medicineand the pharmacodynamic herb-drug interactions caused bytwo different medicines working in the same or oppositedirections and ultimately affecting the dose response andany mechanisms of therapeutic or toxic effects (Figure 1)[35]. For example, St-John’s Wort, a well-known cytochromeP450 inducer, may affect systemic bioavailability of manyconventional drugs [60].

Common examples of herb-drug interactions have beenfound when cardiovascular medications with a narrow ther-apeutic index, such as digoxin and warfarin, are coadminis-tered with herbs. For instance, concomitant use of warfarinwith St. John’s Wort decreases prothrombin time, which mayresult in reduced anticoagulant effect and need for increasedwarfarin dose [61]. Other examples of interactions include St.John’s Wort with cyclosporine [62] and grapefruit juice withfelodipine and lovastatin [63].

The current evidence that herbal medicine may interactwith conventional drugs is mainly based on case reportsof patients, case series, and a limited number of clinicalstudies. Drug-herbal interactions are difficult to evaluate

because of the lack of compositional reliability of the herbalproducts though anumber of interactions, amongstwhich aredrug-metabolizing enzymes and drug transporter systems,as well as pharmacodynamic interactions can be involved.However since the pharmacokinetic and pharmacodynamiccharacteristics of most herbal medicine or supplements arenot completely recognized, potential interactions cannot bepredicted.

In a clinical study involving 313 patients, Jeong et al. [64]concluded that herbal drugs used alone were relatively safe,but the risk for adverse reactions may increase when herbaland conventional drugs are taken concurrently. The resultsindicated a 2.3% incidence of liver injury in the combinedgroup of Korean patients. Concomitantly, Zhu et al. [65]reported that rutaecarpine, an alkaloid found in Evodiarutaecarpa traditionally used in combination with Chinesetraditional medicine, had profound effects on the hepaticdrug processing enzyme gene expression, CYP enzyme genesand UDP-glucuronosyltransferase, and increased the expres-sion of hepatic uptake and efflux transporters. The authorsspeculated that all these effects could play an integratedrole in rutaecarpine-increasedmetabolismand elimination ofcaffeine [66], theophylline [67], and acetaminophen [68].

From evidence-based herb-drug interaction in cancerchemotherapy, Cheng et al. [59] concluded that most ofthe available information, both positive and negative, camefrom basic in vitro experiments or trials testing the useof a single herb along with chemotherapy drug when inpractice most of the herbs are used in mixtures. The latterargued that “it is not reasonable to discard the potentialusefulness of the traditional wisdom of herbal medicine,which has the backing of thousands of years of clinicalexperience.” However, this statement should be taken withsome level of skepticism particularly since clinically relevantpharmacokinetic interactions between anticancer drugs andCAM have already been reported between the frequentlyused St. John’s Wort and the anticancer drugs irinotecan [69]and imatinib [70]. This justifies the need for clinical studiesfor confirmation and assessment of the clinical relevance ofCAM-drug interactions obtained in vitro and emphasizedrecently by Goey et al. [71].

4. The Way Forward For Developing Countries

Due to the wide use and easy availability of herbal medicines,herbal toxicity and herb-drug interactions have become anissue of global concern. While HMPs provide opportunitiesfor complementing the armoury of existing drugs, for theirpurportedly preventive and therapeutic purposes, the majorproblem with the use of herbal-based treatments is the lackof definite and complete information about the compositionof extracts, resulting mainly from the trade secrecy of anumber of herbal practitioners. Despite the fundamental rolethat traditional medical practitioners play in the provisionof health services in developing countries, trade secrecyhas been observed and is currently encroaching on theproper assessment of local herbal drugs. The lack of GoodManufacturing Practices, Good Agricultural Practices, Good


Drugs

Herbal products

Interaction between herbal products and medication

Pharmacodynamic drug interactions Pharmacokinetic drug interactions

Absorption Additive, synergistic, or antagonistic activity

ExcretionProtein bindingMetabolismDistribution

Related to metabolizing enzymes and drug transporters

Impaired absorption when herbs contain

hydrocolloidal fibers, gums, or mucilage

Drug

drugs

displacement of protein-bound

Cytochrome P450 P-Glycoprotein

Transmembrane efflux transporter

Change in renal clearance

Pharmacological activity altered

Organ systems Enzymes Receptor sites

Figure 1: Generalised mechanistic insight into herb-drug interactions.

Laboratory Practices, and metabolic, pharmacokinetic, andtoxicologic characteristics further characterized the dangersof HMPs in developing countries.

Hence, in many developing countries involved with theactive production and use of HMPs, regulations distinct fromthe one for food and drugs are warranted. The existence ofsuch regulation can emphasise a premarket system, whichprovides market authorisation for each HMP based onevidence that the product is safe under the recommendedconditions of use without a prescription, effective for theproposed claims, and of high quality, and is mandatory. Inaddition, a licence issued on the basis of evidence of compli-ance with GoodManufacturing Practices to importers, man-ufacturers, packagers, and labellers ofHMPswill certainly aidin reducing health-related risks. Such an effort should be inconcert withWHO International Regulatory Cooperation forHerbal Medicines (IRCH), established in 2005 to protect andpromote public health and safety [72].

There is also a strong need for scientific evidence ofthe pharmacological qualities and safety of herb-derivedremedies employed for centuries as traditional medicines inthese countries.This is particularly because sound knowledgeof the mechanisms of actions and interactions is essentialfor a clinical risk assessment. In addition, the design ofan appropriate postmarket pharmacovigilance system willhelp address the fatalities of herbal drugs. Surveillance for

HMP-related adverse responses should consist mainly ofprompting voluntary reporting from consumers and healthcare practitioners. It should be noted that even if theinteractions between medicinal herbal products and drugsmay be clinically insignificant, susceptibility to them may beenhanced by a wide variety of patient-related factors, such asthe presence of multiple diseases, other pharmacotherapies,or genetic predisposition.

At the same time, it would be helpful to set up a nationaland/or regional accessible database to document the use ofherbal medicines. Concurrently, efforts should be made toeducate both healthcare professionals and patients about theuse of herbal medicine. It should also be emphasised thatbesides its role in primary healthcare, traditional medicineshave been and continue to be a strategic option in drugdiscovery [73].

The previously mentioned long-term strategies couldcertainly help to address the toxicological concern of herbaldrugs in developing countries. But more immediate actionsare also warranted and should be geared towards (1) greatercommunication between patients and physicians about theuse of herbal medicine, (2) health care professional shouldbe aware of herb-drug interactions and encourage patientsto discuss herbal medicine use, (3) physicians should ques-tion patients about their use of herbal medicines, and (4)surveillance of HMP-related adverse responses should be


monitored. In the meantime, preclinical and clinical studiesshould be conducted to ascertain herb-drug interactions andgovernment regulatory authority should putmore efforts intonatural health product regulations.

Conflict of Interests

The author declares that there is no conflict of interests.

Acknowledgments

The author wishes to thank Miss Rima Beesoo and MissSrishti Ramsaha for compiling data for Tables 1 and 2.

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Review Article Underestimating the Toxicological Challenges ...assessment of herbal medicine [ , ]. Apart from the toxicity of the intended herb(s) itself, the lack of a stringent